AB0013 THE COHESIN COMPLEX PROTEIN SMC1A IS A PUTATIVE REGULATOR OF SEX-BIASED INFLAMMATORY RESPONSES IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: D. Kosmara, C. Stathopoulou, S. Papanikolaou, G. Vatsellas, A. Banos, P. Sidiropoulos, D. Boumpas, D. Konstantopoulos, G. Bertsias
Journal: Annals of the Rheumatic Diseases (2022)

Background A strong female predisposition is characteristic of Systemic Lupus Erythematosus (SLE), with female-to-male ratio ranging from 7:1 to 15:1. The molecular basis of this gender bias remains incompletely understood. In a previous whole-blood RNA profiling study, we identified genes with differential expression in SLE males versus females but not in their healthy counterparts. Among these genes, the cohesin complex protein SMC1A (Structural Maintenance of Chromosomes 1A) displayed the highest statistical significance [1]. Objectives To (a) determine the immune cell type that displays the strongest gender-biased SMC1A expression in SLE versus healthy individuals, and (b) elucidate the role of SMC1A in regulating immune/inflammatory responses in the context of SLE. Methods Multiple immune cell types (CD19 + B cells, CD4 + T cells, CD14 + monocytes, neutrophils) were purified from peripheral blood specimens of SLE and healthy individuals, followed by Taqman PCR and Western blot to measure SMC1A mRNA and protein levels, respectively. The genome-binding properties of SMC1A were assayed by chromatin immunoprecipitation (ChIP)-sequencing in monocytes cultured under lupus-inducing conditions (lupus-like monocytes) [2]. To recapitulate the female/male difference in SMC1A expression, ex vivo cultured lupus-like monocytes were transfected with si-SMC1A (to downregulate SMC1A) versus si-control reagent, followed by genome-wide transcriptome analysis by RNA-sequencing. Results Among the various tested immune cell types, CD14 + monocytes best recapitulated the initial whole blood RNA-seq findings, demonstrating significantly decreased SMC1A mRNA and protein expression in male versus female SLE patients but not in their healthy counterparts. In blood monocytes cultured under lupus-inducing conditions and tested by ChIP-sequencing, SMC1A binding was increased on enhancers and promoters of genes associated with inflammation (including type I/II interferon and other inflammatory cytokines) and cell migration. In accordance, lupus-like monocytes with lowered SMC1A expression (i.e., male-like) displayed significantly reduced expression of inflammatory genes like IL6 , GBP5 , ADA and IL1A , as compared to monocytes with unaffected SMC1A (i.e., female-like). Furthermore, IL6 mRNA synthesis was significantly enhanced in female versus male monocytes cultured under lupus-inducing conditions. Conclusion SMC1A may transcriptionally regulate genes associated with the inflammatory response of monocytes. Our findings of gender-biased SMC1A levels in SLE monocytes raise the hypothesis that differential SMC1A expression and function might contribute to the disease gender bias and/or sexual dimorphism. References [1]Panousis NI, et al. Ann Rheum Dis. 2019 Aug;78(8):1079-1089. [2]Park SH, et al. Nat Immunol. 2017 Oct;18(10):1104-1116. Acknowledgements The current work is funded by the Hellenic Foundation for Research &amp; Innovation (HFRI). This research is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (IΚΥ) Disclosure of Interests None declared